Parkinson Disorders Research Program, Iowa Center for Advanced Neurotoxicology, Department of Biomedical Sciences, Iowa State University, Ames, Iowa 50011, USA.
School of Biomedical Sciences, The University of Queensland, Brisbane, Queensland 4072, Australia.
Nat Commun. 2016 Oct 5;7:12932. doi: 10.1038/ncomms12932.
Prokineticin-2 (PK2), a recently discovered secreted protein, regulates important physiological functions including olfactory biogenesis and circadian rhythms in the CNS. Interestingly, although PK2 expression is low in the nigral system, its receptors are constitutively expressed on nigrostriatal neurons. Herein, we demonstrate that PK2 expression is highly induced in nigral dopaminergic neurons during early stages of degeneration in multiple models of Parkinson's disease (PD), including PK2 reporter mice and MitoPark mice. Functional studies demonstrate that PK2 promotes mitochondrial biogenesis and activates ERK and Akt survival signalling pathways, thereby driving neuroprotection. Importantly, PK2 overexpression is protective whereas PK2 receptor antagonism exacerbates dopaminergic degeneration in experimental PD. Furthermore, PK2 expression increased in surviving nigral dopaminergic neurons from PD brains, indicating that PK2 upregulation is clinically relevant to human PD. Collectively, our results identify a paradigm for compensatory neuroprotective PK2 signalling in nigral dopaminergic neurons that could have important therapeutic implications for PD.
胃动素-2（PK2）是一种最近发现的分泌蛋白，可调节包括嗅觉发生和中枢神经系统昼夜节律在内的重要生理功能。有趣的是，尽管 PK2 在黑质系统中的表达水平较低，但它的受体在黑质纹状体神经元中持续表达。在此，我们证明，在包括 PK2 报告小鼠和 MitoPark 小鼠在内的多种帕金森病（PD）模型的早期退行性变过程中，PK2 在黑质多巴胺能神经元中高度诱导表达。功能研究表明，PK2 促进线粒体生物发生，并激活 ERK 和 Akt 存活信号通路，从而驱动神经保护。重要的是，PK2 的过表达具有保护作用，而 PK2 受体拮抗作用则加剧了实验性 PD 中的多巴胺能变性。此外，PD 大脑中存活的黑质多巴胺能神经元中的 PK2 表达增加，表明 PK2 的上调与人类 PD 具有临床相关性。总之，我们的研究结果确定了一种在黑质多巴胺能神经元中补偿性神经保护 PK2 信号的范例，这可能对 PD 具有重要的治疗意义。
